Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982 from porcine brain [K. Takemoto, Proc. Nat. Acad. Sci., (1982) 79, 5485-5489; D. R. Gehlert, Life Sciences, (1994) 55, 551-62; L. Grundemar and R. Hak.ang.nson, TiPS, (1994) 15, 153-159; J. M. Lundberg, TiPS, (1996) 17, 301-304; C. Wahlestedt and D. J. Reis, Ann. Rev. Pharmacol. Toxicol., (1993) 32, 309-352; P. A. Hipskind, Ann. Rep. Med. Chem., (1996), 31, 1-10; J. D. White, Regulatory Peptides, (1993) 49, 93-107; A. Sahu and S. P. Kalra, Trends Endocrinol. Metab., (1993) 4, 217-224; Y. Dumont, J.-C. Martel, A. Fournier, S. St. Pierre and R. Quirion, Prog. Neurobiol., (1992) 38,125-167; M. C. Michel and A. Buscher, Drugs of the Future, (1992) 17, 39-45; M. C. Michel, TiPS, (1991) 12, 389-394; J. Lehmann, Drug. Dev. Res., (1990) 19, 329-351; G. Williams, Peptides, (1995) 4, 757-771]. The peptide is a member of a larger peptide family which also includes peptide YY (PYY), pancreatic peptide (PP), and the non-mammalian fish pancreatic peptide Y (PY). Neuropeptide Y is very highly conserved in a variety of animal, reptile and fish species. It is found in many central and peripheral sympathetic neurons and is the most abundant peptide observed in the mammalian brain. In the brain, NPY is found most abundantly in limbic regions. The peptide has been found to elicit a number of physiological responses including appetite stimulation, anxiolysis, hypertension, and the regulation of coronary tone.
Structure-activity studies with a variety of peptide analogs (fragments, alanine replacements, point mutations, and internal deletion/cyclized derivatives) suggest a number of receptor subtypes exist for NPY [L. Grundemar and R. Hak.ang.nson, TiPS, (1994) 15, 153-159]. These currently include the Y.sub.1, Y.sub.1-like, Y.sub.2, Y.sub.3, and the Y.sub.4 subtypes.
Although specific peptidic antagonists have been identified for most of the subtypes, few selective non-peptidic antagonists have been reported to date. Several competitive but non-selective, non-peptidic antagonists are known. The heterocyclic guanidine derivative He 90481 (4) was found to be a weak but competitive antagonist of NPY-induced Ca.sup.++ entry in HEL cells (pA.sub.2 =4.43) [M. C. Michel and H. J. Motulsky, Annu. Rev. N.Y. Acad. Sci., (1990) 611, 392-394; U.S. Pat. No. 4,912,119, 1990 (Heumann Pharma GMBH)]. The compound was also found to have .alpha..sub.2 -adrenergic and histaminergic activity at this dose range. D-Myo-inositol-1,2,6-triphosphate (5) was reported to be a potent but non-competitive antagonist to NPY-induced contractions in guinea pig basilar artery [L. Edvinsson, M. Adamsson and I. Jansen, Neuropeptides, (1990) 17, 99-105]. Similarly, the benextramine-like bisguanidines 6a and 6b were reported to displace .sup.3 H-NPY in rat brain (IC.sub.50, 19 and 18.4 .mu.M) and to display functional antagonism in rat femoral artery [M. B. Doughty, C. Chaurasia and K. Li, J. Med. Chem., (1993) 36, 272-79; M. B. Doughty, S. S. Chu, G. A. Misse and R. Tessel, BioMed. Chem. Lett., (1992) 2, 1497-1502; C. Chaurasia, G. Misse, R. Tessel and M. B. Doughty, J. Med. Chem., (1994) 37, 2242-48]. The bisguanidine 6b was shown to be functionally selective for the Y.sub.2 receptor since it antagonized the effect of the NPY.sub.2 agonist NPY.sub.13-36 but had no effect on the vasoconstrictive activity of the NPY.sub.1 agonist [Leu31, Pro34]NPY [C. Chaurasia, G. Misse, R. Tessel and M. B. Doughty, J. Med. Chem., (1994) 37, 2242-48].
A substantial body of art has accumulated over the past two decades with respect to 4-aryl-1,4-dihydropyridine compounds. A large number of these possess calcium antagonist properties and find utility in the treatment of cardiovascular diseases. Several 4-aryl-1,4-dihydropyridines with piperidine-ring-containing-substituents have been reported.
A series of compounds of formula (1) was claimed to be ##STR2##
useful as vasodilators, antihypertensives and diuretics by Flockerzi, et al., in U.S. Pat. No. 4,707,486, issued Nov. 17, 1987.
A series of dihydropyridines, including compounds of formula (2), were disclosed and claimed to have antitumor promoting activity in European Patent Application 533,504, published on Mar. 24, 1993. ##STR3##
European Patent Application 534,520, published on Mar. 31, 1993, discloses related compounds having formula (3) wherein R.sup.5 is alkyl, phenyl and aralkyl. ##STR4##
A compound of formula (4) has been disclosed in JO 4049-237-A, published on Jun. 15, 1990, and claimed to be an inhibitor of Phospholipase A.sub.2. ##STR5##
Of less significance is a series of antihypertensive dihydropyridine anilide derivatives disclosed by Szilagyi, et al, in U.S. Pat. No. 4,829,076, issued May 9, 1989, and containing compounds of formula (5) ##STR6##
in which B is a chemical bond or an alkylene group.
A guanidine derivative of formula (6) having NPY-Y.sub.1 selective receptor antagonist activity was ##STR7##
disclosed by Rudolf, et al. Eur. J. Pharmacology, (1994) 271, R11-13.
A series of substituted benzylamine derivatives of the general formula (7) having NPY-Y.sub.1 receptor antagonist activity ##STR8##
was disclosed by Peterson, et al. in International Patent Application WO 96/14307, published May 17, 1996.
A series of 4-phenyl-1,4-dihydropyrimidinones derivatives of the general formula (8) having NPY-Y.sub.1 receptor antagonist activity ##STR9##
was disclosed by Bruce, et al, in U.S. Pat. No. 5,889,016, issued on Mar. 30, 1999, and claimed to promote weight loss and treatment of eating disorders.
These reference compounds are readily distinguished structurally from the compounds of the instant invention by virtue of many of the art compounds having the piperidine substituents attached to the dihydropyridine ring itself or to a phenyl ring which is attached to a dihydropyridine ring or a dihydropyrimidone ring. In contrast, compounds of the instant invention contain piperidine or piperazine moieties attached to the 3-position of the 4-phenyl ring which is then attached to a dihydropyrazine ring. Not only are the present compounds structurally novel, they also have been discovered to possess novel NPY antagonist activity.
In summary, the prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel dihydropyrazine derivatives as having good antagonist activity at NPY-Y.sub.1 receptor sites.